Kidney International, Vol. 56 (1999), pp. 1863–1871
CLINICAL NEPHROLOGY – EPIDEMIOLOGY – CLINICAL TRIALS
Spectrum of disease in familial focal and
segmental glomerulosclerosis
PETER J. CONLON, KELVIN LYNN, MICHELLE P. WINN, L. DARRYL QUARLES, MARY LOU BEMBE,
MARGARET PERICAK-VANCE, MARCY SPEER, and DAVID N. HOWELL, on behalf of the
INTERNATIONAL COLLABORATIVE GROUP FOR THE STUDY OF FAMILIAL FOCAL AND
SEGMENTAL GLOMERULOSCLEROSIS1
Department of Medicine and Center for Human Genetics, Duke University Medical Center; Department of Pathology, Duke
University Medical Center and Durham Veterans Hospital, Durham, North Carolina, USA; and Department of Medicine,
Christchurch Hospital, Christchurch, New Zealand
Spectrum of disease in familial focal and segmental glomerulosclerosis.
Background. Focal segmental glomerulosclerosis (FSGS) is
the underlying pathologic entity in 5% of adults and 20% of
children with end-stage renal disease (ESRD). FSGS is generally considered to be sporadic in origin.
Methods. Recently, we identified 60 families involving 190
1
The participating physicians in the Collaborative Research Group
were as follows:
North America:
Dr. Bill Bennett and Dr. Ahmed Alkhunaizi (Portland, OR, USA);
Dr. Darol Joseff (Santa Barbara, CA, USA); Dr. Mark Arons (Pinehurst, NC, USA); Dr. Restaino (Norfolk, VA, USA); Dr. John Foreman,
Dr. Delbert Wigfall, Dr. Steve Smith, and Dr. David Butterly (Durham,
NC, USA); Dr. Uri Alon (Kansas City, MO, USA); Dr. Norman Wolfish
(Ottawa, Canada); Dr. Stanton Schultz (Evansville, IN, USA); Dr.
Jeffery Addison (Anniston, AL, USA); Dr. Pierre Faubert (Brooklyn,
NY, USA); Dr. Michael Freundlich (Margate, FL, USA); Dr. James
Smelser (Huntsville, AL, USA); Dr. David Warnock (Birmingham,
AL, USA); Dr. Thomas Amato (Los Angeles, CA, USA); Dr. Paul
Grimm (Winnipeg, Canada); Dr. Jeffrey Harris (Winchester, VA, USA);
Dr. Roger Rodby (Chicago, IL, USA); Dr. James Cain (Roanoke, VA,
USA); Dr. Dennis Geary (Toronto, Canada); Dr. Patrick Parfrey and
Ms. Donna Hefferton (Newfoundland, Canada).
Europe:
Professor Y. Pirson (Louvain, Belgium); Dr. Berbagui Hamid (Lyons,
France); Dr. Paul Stevens (Canterbury, England, United Kingdom);
Dr. Neemiye Tumer (Ankara, Turkey); Dr. Stephen Segerer (Munich,
Germany); Dr. Rainer Valentin (Germany); Dr. Phil Kalra and Dr.
Nick Pritchard (Salford, England, United Kingdom); Dr. Vincent Bosteels and Dr. Louis Janssens (Kortrijk, Belgium); Dr. Kurt Vandepitte
(Lier, Belgium); Dr. Nick Plant (Newcastle, England, United Kingdom).
Other countries:
Dr. Kelvin Lynn and Dr. Ross Bailey (Christchurch, New Zealand);
Dr. Robert Walker (Dunedin, New Zealand); Dr. Grant Pidgeon (Wellington, New Zealand); and Dr. Abdias Arestegui (Lima, Peru).
Key words: glomerulonephritis, renal disease, genetics, FSGS, inherited FSGS.
Received for publication November 13, 1998
and in revised form April 7, 1999
Accepted for publication May 20, 1999
 1999 by the International Society of Nephrology
individuals with familial FSGS, providing evidence for a subset
of families in which a genetic form is segregating. Each family
had at least one member with renal biopsy-confirmed FSGS
and at least one other member with either renal biopsy-confirmed FSGS or ESRD.
Results. Twenty-six families had individuals affected in more
than one generation [multigeneration (MG)], and the remaining 34 families had only a single generation (SG) affected.
There was equal representation of males and females among
affected individuals. Ten percent of MG families were African
American, and 52% of SG families were African American.
The mean age of presentation was significantly higher in the
MG families (32.5 6 14.6 years) compared with the SG families
(20.1 6 12.1 years, P 5 0.0001). SG cases had higher levels of
proteinuria at presentation (7.0 6 5.6 g/24 hr, compared with
3.8 6 3.4 g/24 hr, for the MG families, P 5 0.002). On renal
biopsy, tubulointerstitial damage was more severe in patients
in the SG families than in the MG families; however, the level
of glomerular damage did not differ between these groups.
Fifty percent of the patients had progressed to ESRD by the
age of 30 years. Variables measured at presentation that were
independently associated with poor renal survival were decreased age, increased serum creatinine, and increased urinary
protein excretion. Forty-one patients underwent successful renal transplantation, with a 10-year graft survival rate of 62%.
One patient developed clinical and biopsy evidence of recurrence of FSGS in the allograft.
Conclusion. These data confirm the existence of a nonAlport’s form of hereditary glomerulonephritis, which has a
morphological pattern of FSGS.
Focal segmental glomerulosclerosis (FSGS) is a primary glomerular disease of unknown etiology with a population incidence of approximately two per million [1–3].
FSGS is a major cause of end-stage renal failure, particularly in young people [4], accounts for at least 2.5% of
all cases of end-stage renal disease (ESRD), and it is
refractory to treatment. It has been reported in patients
of varied ethnic backgrounds, including American Caucasian, European, Hispanic, and African American [5, 6],
1863
1864
Conlon et al: Familial FSGS
although it appears to be more frequent among African
Americans than among other ethnic groups [6, 7]. The
etiology of FSGS is poorly understood: It is unclear
whether FSGS is the result of a systemic disease or an
intrinsic defect of the glomerulus [8–10].
Although it is well recognized that genetics plays an
important role in the development of many forms of
renal disease [11–13], FSGS has, until recently, been
considered to be primarily a sporadic disorder. Recently,
we reported a number of families in which FSGS affected
multiple members within the same family (multiplex
FSGS families) [14]. The occurrence of FSGS in multiple
members of the same family has also been observed by
a number of other authors [15–26]. The identification of
large pedigrees with familial FSGS (FFSGS) may allow
the application of positional cloning technology to identify the underlying molecular pathogenesis of FSGS. We
have recently developed an international collaborative
group to study this syndrome. Here we present our findings with respect to family history, clinical and associated
pathological findings, and their relationship to the longterm prognosis in this large series of multiplex FSGS
families.
METHODS
Patients
Families that contained at least two individuals who
carried a diagnosis of FSGS, as defined later in this article, were ascertained. Sixty families were identified
through a variety of sources and referral patterns. Advertisements were placed in the leading nephrology journals
and on the “NEPHROL” e-mail nephrology discussion
group. Cases were identified from the published literature. Information regarding additional patients was obtained from the clinics and medical personnel in the
Division of Nephrology at Duke University Medical
Center. In order to be included in this analysis, each
family needed to have at least one member with biopsyproven FSGS and either a second member with biopsyconfirmed FSGS or other family members with ESRD.
Individuals were excluded if they had any secondary
form of FSGS such as those associated with HIV infection, reflux nephropathy, sickle cell disease, or intravenous drug use.
A detailed family history was obtained from all participating families. Medical records and renal pathological
material were obtained when available to confirm the
diagnosis and family history reports. The medical records
of all of these subjects were reviewed to identify factors
pertaining to the clinical presentation of the disorder,
associated syndromes, natural history, pattern of inheritance, and outcome following renal transplantation. Hypertension was considered to be present if at presentation
the subject was taking antihypertensive medication or had
a resting blood pressure of greater than 140/90 mm Hg.
All family history and clinical data were recorded in a
database using the Pedigene system. As many first-degree relatives as were available were studied for the
presence of occult renal disease by the qualitative analysis of a freshly voided urine specimen for proteinuria.
Subjects who were demonstrated to have 21 or greater
proteinuria were invited to have a more complete
nephrological evaluation, including renal biopsy where
appropriate.
Within these families, subjects were classified as definitely affected, probably affected, status unknown, and
probably unaffected.
Definitely affected. Subjects who had a renal biopsy
demonstrating FSGS in the absence of evidence for secondary FSGS were classified as definitely affected.
Probably affected. Family members with ESRD requiring renal replacement therapy, who had not undergone renal biopsy, or family members with 3 or 41 proteinuria on a urine dipstick in the absence of other
systemic disease likely to lead to proteinuria (such as
diabetes or lupus) were classified as probably affected.
Status unknown. Family members with 1 or 21 proteinuria or with 500 mg or less of proteinuria on a 24hour collection were classified as status unknown.
Probably unaffected. Subjects within these families
without evidence of proteinuria on dipstick urinalysis
were classified as probably unaffected.
This report focuses on definitely affected or probably
affected individuals.
Families were classified according to whether there
was evidence that individuals from one or more generations were affected. Families with multiple generations
(MG) affected had to have clear-cut evidence of vertical
transmission of the trait, with individuals from two or
more generations affected, based on the definitions given
previously in this article. Families with single generation
(SG) involvement had no more than one generation
demonstrating any manifestation of disease. This classification (SG) was applied only where the parents of the
individuals were available for examination and/or urinalysis and were demonstrated to be free of renal disease
or the parent died at an advanced age and was known
to have died of a nonrenal cause. Individuals whose
parents were not available for examination or in whom
the cause of death was not available were excluded.
Pathological data
The histological diagnosis of FSGS was based on the
criteria of Churg, Habib, and White and required the
presence of areas of glomerular sclerosis or tuft collapse
that were both focal (involving only a subpopulation of
glomeruli) and segmental [7]. Segmental hyalinosis was
present in several cases, but was not considered a requirement for the diagnosis. Morphological features considered
Conlon et al: Familial FSGS
ancillary factors supporting the diagnosis of FSGS included the detection of focal, segmental glomerular
staining for immunoglobulin M and/or C3 by immunofluorescence microscopy and the presence of epithelial
cell foot process effacement by electron microscopy.
Glomerular sclerotic lesions were further classified according to the presence or absence of “collapsing” features [27, 28]. Glomerular lesions were considered to
be of the collapsing variety if they had wrinkling and
“collapse” of the glomerular capillary walls with prominent hypertrophy and hyperplasia of the overlying visceral epithelial cells, often accompanied by intracytoplasmic protein resorption droplets.
In each case, possible underlying causes of segmental
glomerulonephritis (for example, immune complex deposition, antiglomerular basement membrane antibodies, vasculitis) and other potential causes of segmental
glomerular pathology (such as Alport’s syndrome) were
ruled out to the fullest extent possible on clinical and
histological grounds.
Renal biopsies were performed and processed in a
standard fashion, and each was reviewed by an experienced renal pathologist (D.H.) without regard to clinical
information. Histological features were graded by calculating the percentage of glomeruli exhibiting a particular
histological finding (global or segmental collapse or
global or segmental glomerulosclerosis) and by semiquantitative analysis (using a scale of 0 to 31) for the
following features: visceral epithelial hypertrophy, mesangial hypercellularity, synechiae, hyalinosis, tubular
microcysts, tubular epithelial degenerative and regenerative changes, tubular atrophy, interstitial edema, interstitial inflammation, interstitial fibrosis, and arteriolar sclerosis. These were recorded 0 for absent, 1 for ,20%, 2
for 20 to 50% and 3 for .50% of the biopsy surface
affected.
Statistical analysis
Survival times were calculated as the time to initiation
of dialysis, renal transplantation, or death, whichever
came first. In subjects not reaching ESRD, the date of
last follow-up was taken as the date of censoring.
Kaplan–Meier product-limit survival times were calculated using SAS PROC LIFETEST (Cary, NC, USA).
Risk ratios were calculated using the Cox proportional
hazards model, which was also used to test for the influence of multiple risk factors on survival. The log rank
test was used to compare survival curves. Differences
between groups were assessed using the chi-square test
and Student’s t-test as appropriate. A P value of , 0.05
was considered significant.
RESULTS
Clinical presentation
Clinical and pathological data were available on 60
families involving 190 affected individuals. In addition,
1865
260 family members were examined and had urinalysis.
These families were living in the United States (N 5
33), the United Kingdom (N 5 5), Belgium (N 5 4),
New Zealand (N 5 4), France (N 5 3), Germany (N 5 1),
Turkey (N 5 1), Peru (N 5 6), and Canada (N 5 3).
One hundred and four subjects were considered to
be definitely affected, and 86 were considered probably
affected (vide supra). A total of eight family members
previously considered unaffected were identified as
probably affected as a result of screening for proteinuria.
Twenty-six families had individuals affected from MG.
Figure 1 displays the pedigree of our largest family, involving 37 affected individuals. In the remaining 34 families, only individuals from an SG were affected. The
transmission of the trait from both males and females
to both male and female children was observed, thus
excluding either a sex linkage or a mitochondrial DNA
disorder.
Six families contained one set of twins each. Two of
these sets were dizygotic twins, and in each of these
families one member of the twin set was affected. Both
members of the twin set were affected in three of the
four sets of monozygotic twins. In the one discordant
identical twin set, the affected was 11 years of age and
had 5 g of protein excretion with normal renal function.
Her father developed ESRD secondary to biopsy-proven
FSGS. The apparently unaffected child had been followed for two years and had no protein excretion on
dipstick.
In only one family, the development of FFSGS was
associated with a dysmorphic syndrome. This was in two
children ages 22 months and 9 months who developed
FSGS with nephrotic syndrome. They were the children
from the marriage of first cousins, and had congenital
microcephaly, hypotonia, poor neurological development, and low-set ears in addition to nephrotic syndrome.
Clinical features at presentation were compared between SG and MG cases. SG subjects presented at a
younger age (20.1 6 12.1 vs. 32.5 6 14.6 years, P 5
0.0001; Fig. 2), had heavier proteinuria (7.0 6 5.6 vs.
3.8 6 3.4 g/24 hr, P 5 0.002), and were more likely to
be hypertensive (82 vs. 60%, P 5 0.01) than individuals
within MG families (Table 1). There was no difference
in serum creatinine between SG and MG individuals.
Pathologic features
A total of 104 patients underwent renal biopsy, of
which 68 had electron microscopy and immunofluorescence examinations in addition to light microscopy. Renal pathology slides were available for review by us from
88 biopsies performed on 75 patients, and the renal pathology reports were reviewed on the remainder. The
number of renal biopsies per family ranged from 1 to
15. Thirteen patients had two or more renal biopsies.
1866
Conlon et al: Familial FSGS
u
Fig. 1. Pedigree of largest multigeneration family in the series. Symbols are: (j) affected male; (d) affected female; (h) unaffected male; (s) unaffected
female; (h ) deceased.
Histological examination of biopsy tissue revealed a
wide variety of glomerular and extraglomerular abnormalities. Segmental sclerosis was identified in biopsies
from 52% of patients with FFSGS, and segmental or
global collapse was seen in biopsies from 11%; both
segmental sclerotic and collapsing lesions were seen in
biopsies from 15% of the patients. In all, 78% of the
patients had evidence of either segmental sclerosis or
collapse. The mean percentages of segmentally sclerotic
glomeruli and glomeruli with segmental and/or global
1867
Conlon et al: Familial FSGS
Fig. 2. Age at presentation of patients with
familial focal segmental glomerulosclerosis
(FFSGS). Symbols are: (j) single generation
inheritance; (h) multigeneration inheritance.
Table 1. Clinical variables measured at presentation
Race % black
Sex % male
Age at presentation years
Serum Cr at presentation mg/dl
Proteinuria at presentation g/24 hr
Hypertension
Multigeneration
(N 5 125)
Single generation
(N 5 65)
P
10.1
44
32.5 6 14.6
4.1 6 5.7
3.8 6 3.4
60%
52
43
20.1 6 12.1
3.0 6 3.7
7.0 6 5.6
82%
0.001
0.5
0.0001
0.2
0.002
0.01
Table 2. Histology of familial FSGS: Glomerular
Of all glomeruli
Global collapse %
Segmental collapse %
Global sclerosis %
Segmental sclerosis %
21 or greater on semiquantitative analysis
Visceral epithelial hypertrophy
Mesangial hypercellularity
Multigeneration
Single generation
P
2.5 6 5.7
2.8 6 6.3
19.7 6 21.9
10.9 6 10.5
12 6 22.1
5.2 6 7.6
27.2 6 33.4
9 6 12.2
0.07
0.2
0.4
0.3
9.3
0
5.8
0
0.1
NS
collapse did not differ significantly between SG and MG
groups (Table 2). Globally sclerotic glomeruli were a
common feature in both groups, constituting 19.7 6
21.9% of the glomeruli in the MG biopsies and 27.2 6
33.4% in the SG group (P 5 0.4).
In biopsies from 9% of patients, global glomerular
sclerosis was the only lesion identified. In half of these,
all of the glomeruli were globally sclerotic. In an additional 5% of biopsies, no significant glomerular lesions
were identified, possibly as a result of sampling early in
the course of the disease. The remaining 8% of biopsies
contained insufficient tissue for a definitive diagnosis.
A variety of tubulointerstitial changes was also noted
in the biopsies (Table 3). Of particular note were tubular
degeneration/regeneration, tubular atrophy, interstitial
inflammation, and interstitial fibrosis, all of which were
significantly more prevalent in biopsies from the SG
group than those from the MG group. Prominent tubular
microcyst formation and interstitial edema were noted
in only a small fraction of the biopsies and did not differ
significantly between the two groups. Extensive arteriolar sclerosis was seen in occasional biopsies, with approximately equal frequency in the two groups.
Renal survival
Ninety-three individuals developed ESRD. The median age for the development of ESRD was 30 years.
Variables measured at the presentation that were significantly associated with worse renal survival (Table 4)
included decreased age of presentation, single-generation involvement (Fig. 3), increased serum creatinine,
increased urinary protein excretion (Fig. 4), and black
race (Fig. 5). None of the pathological variables were
significantly associated with prolonged renal survival.
Using backward elimination from the Cox proportional
hazards model (Table 5), the following variables were
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Conlon et al: Familial FSGS
Table 3. Histology of familial FSGS: Tubulointerstitial
Multigeneration
Single generation
P
0
1%
3.6%
0
3.1%
4.6%
6.1%
2%
9%
18%
5.3
16.3%
17.8%
8.9%
0.6
0.03
0.002
0.9
0.004
0.0039
0.3
21 or greater on semiquantitative analysis
Tubular microcysts
Tubular degeneration/regeneration
Tubular atrophy
Interstitial edema
Interstitial inflammation
Interstitial fibrosis
Arteriolar sclerosis
Table 4. Clinical variables associated with progression to end-stage
renal disease (ESRD)
Risk ratio
(95% CI)
a
Age
Creatinine
SG vs. MG
Proteinuria
Sex (male vs. female)
Race (white vs. other)
Hypertension (present vs. absent)
0.66
1.04
0.3
1.13
(0.7–0.95)
(1.02–1.07)
(0.2–0.4)
(1.1–1.16)
(0.9–1.4)
2.1 (1.7–2.7)
(0.8–1.9)
P
0.0001
0.04
0.0001
0.0001
0.4
0.0005
0.4
Abbreviations are: SG, single generation; MG, multigeneration.
a
Risk ratio expressed for 10 unit change.
Fig. 3. Survival based on the pattern of inheritance. Renal survival
was worse in patients with single generation involvement (N 5 65)
compared with families with multigeneration involvement (N 5 125).
independently associated with worse renal survival:
younger age at presentation, increased serum creatinine,
and increased urinary protein excretion.
Outcome of renal transplantation
A total of 41 patients underwent 48 renal transplant
procedures. The 10-year survival of these grafts is outlined in Figure 6. At 10 years, 62% of grafts continued
to function. Only one patient demonstrated a recurrence
of FSGS in the allograft. Two subjects, who initially
appeared unaffected, donated a kidney to an affected
sibling and subsequently developed proteinuria and on
renal biopsy were demonstrated to have FSGS [29]. Both
of these individuals subsequently developed ESRD. The
recipient of one of these kidneys developed chronic allograft rejection secondary to noncompliance with medications, and the other kidney functioned for greater than
10 years.
DISCUSSION
In this report, we present a large series of patients
with multiple family members affected with FFSGS. The
vertical mode of transmission in many of the families
and the development of FSGS in both sets of twins establish this as a clearly genetic disorder, rather than the
result of some environmental exposure. We have observed the frequent development of ESRD in affected
individuals.
In this review, we used the terms SG involvement and
MG involvement, as they make no assumptions about
Fig. 4. Survival based on proteinuria at presentation. Renal survival
was significantly worse in subjects who presented with greater than
3 g of protein excretion per 24 hours (N 5 120) when compared with
those with lesser levels of protein excretion (N 5 70).
pattern of inheritance. It is likely that MG families are
families with autosomal dominant inheritance and that
SG families have autosomal recessive inheritance, although there are also other possibilities, including autosomal dominant with incomplete penetrance. We have
adopted a very conservative technique of labeling families SG in that only families in which both parents were
examined and found to be free of renal disease were
labeled SG. Families with SG involvement appear to
have a more aggressive form of disease, as they presented
at a younger age and with heavier proteinuria than MG
families. It is possible that this apparently more aggressive deterioration in renal function represents ascertainment bias, in that individuals within families already
Conlon et al: Familial FSGS
Fig. 5. Renal survival was significantly worse in African American
subjects when compared with Caucasians.
Table 5. Variables independently associated with progression
to ESRD
a
Age
Creatinine
Proteinuria
a
Risk ratio
(95% CI)
P
0.46 (0.37–0.58)
1.2 (1.1–1.7)
1.13 (1.1–1.5)
0.007
0.01
0.0002
Expressed for 10 unit change.
Fig. 6. Survival of renal allograft in patients with FFSGS.
known to be affected by renal disease are more likely
to be detected early. However, when the survival analysis
was confined to the probands in each family, thus eliminating the effect of ascertainment bias, the same trends
in terms of worse serum creatinine, higher proteinuria,
and earlier age of ESRD were apparent in the SG families when compared with MG families.
The first reports of the occurrence of an autosomal
dominant FSGS came from Walker, Lynn, and Ross in
New Zealand in 1982 [24]. Walker et al reported seven
patients in three families with familial FSGS that was
inherited as an autosomal dominant trait. Prior to this
report, there were a number of reports of non-Alport
hereditary nephropathy in which the renal pathology
was incompletely described because of the absence of
electron microscopic and immunofluorescence examinations [30, 31]. There are now many reports of FFSGS in
diverse parts of the globe [15–26]. Also, there are a
number of reports of multiple members within the same
1869
family being affected by FSGS in the kidney in association with other hereditary defects [15, 32–36]. Because
the disease is uncommon, the aggregation in a family of
more than one affected member is compelling evidence
for a major gene.
The weight of existing evidence in experimental models of FSGS and human sporadic FSGS supports a role
for a circulating factor that results in increased glomerular permeability [8, 9, 37, 38]. The early recurrence of
FSGS after renal transplantation has been observed for
more than 20 years and provides a tantalizing clue that a
circulating substance may be responsible for glomerular
injury in some patients with this entity. Further evidence
for the presence of a circulating factor associated with
FSGS is supported by the effectiveness of plasmapheresis
to treat recurrence of FSGS following renal transplantation [9, 38]. However, unlike sporadic forms of FSGS,
we have observed the recurrence of FSGS in only one
of 41 renal transplant recipients with FFSGS, suggesting
that intrinsic abnormalities of the kidney are responsible
for FFSGS, rather than a circulating factor.
Not every subject in this study underwent a renal
biopsy to confirm the histological pattern of their glomerular injury; however, most families did have at least two
individuals with a renal biopsy. In addition, not every
biopsy was subjected to electron microscopic and immunofluorescence examination; however, at least one
biopsy from each family did undergo electron microscopy, excluding any changes of basement membrane
lamellation or splitting that would be compatible with
Alport’s-type nephropathy. A potential criticism of these
studies is the lack of histological confirmation in every
single affected individual, as many of the cases were
classified as affected on the basis of the presence of
ESRD or proteinuria. However, in an analysis of our
largest pedigree, in which we have determined linkage
to chromosome 11, each affected individual carried
the disease allele, and no unaffected individuals carried
it [39].
Developments in molecular biology have enabled investigators to study genetic disorders by a “reverse genetics approach” or “positional cloning” in which the genetic disorder is initially linked to a chromosome marker.
Subsequently, mapping of the gene may be followed by
identification of the gene itself, the mutations responsible
for the disorder, and finally, the gene product. This approach is particularly suitable for a disorder such as this
in which there is very little understanding of the underlying pathophysiologic mechanisms responsible for the disorder. Recently, Mathis et al employed this approach in
studying a large kindred from Oklahoma (USA) [40].
These investigators found strong evidence for linkage to
chromosome 19q. The clinical features of these patients,
however, were very different than the patients in our
series, in that only a small minority of the patients in
1870
Conlon et al: Familial FSGS
Mathis et al’s study progressed to ESRD. The patients
in the Mathis study were also poorly characterized in
terms of renal pathology. We have also recently demonstrated linkage to chromosome 11q for our large New
Zealand family [39], confirming considerable genetic heterogeneity in the molecular pathogenesis of FFSGS.
The cases of FFSGS that we have described here appear clinically and pathologically similar to the much
more common disorder of sporadic FSGS. The only characteristic that appeared to be different from the sporadic
disorder was the absence of recurrence of FSGS after
renal transplantation, which normally occurs in 35% of
patients with sporadic FSGS. It is possible that that both
sporadic and familial FSGS have the same underlying
molecular pathogenesis.
In summary, we have observed a large series of patients with FFSGS. Further study of these families may
contribute to our understanding of the molecular pathogenesis of sporadic FSGS.
9.
10.
11.
12.
13.
14.
15.
16.
ACKNOWLEDGMENTS
This project was funded in part as a result of a National Institutes
of Health grant NS23660 (M.P.V.). We are grateful to the families
who allowed us to study them, the assistance of physicians who referred
them to us, and the assistance of the staff of the center of Human
Genetics at Duke University Medical Center.
Reprint requests to Dr. Peter J. Conlon, Consultant Nephrologist,
Beaumont Hospital, Dublin 9, Ireland.
E-mail: [email protected]
17.
18.
19.
20.
21.
POSTSCRIPT
We are continuing to recruit families with FFSGS, and we are
anxious to hear from any physicians caring for patients with this disorder. Please contact Dr. Peter J. Conlon, M.D., Beaumont Hospital,
Dublin 9, Ireland. Telephone, 353-1-8377755, and Fax, 353-1-8092899.
E-mail: [email protected]
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